Parkinson's disease (PD) is a neurodegenerative disease that afflicts approximately 4-6 million people worldwide. In the United States, approximately one to two hundred people per 100,000 have PD. Interestingly, the prevalence among Amish people is approximately 970 per 100,000 although the basis for this high rate, be it genetic or environmental, is not known. The prevalence of PD increases in the older population, with approximately 4% of people over the age of 80 suffering from this disease (Davie (2008) Brit Med Bull 86(1) p. 109), although 10% of patients are under 40 years of age (Kumari (2009) FEBS J. 276(22) p. 6455).
Typically a patient diagnosed with PD is identified by several hallmark physical behaviors: bradykinesia, rigidity and rest tremor. Often these physical symptoms are asymmetric. Within the brain, PD is characterized by a progressive and profound loss of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta with the presence of eosinophillic, intracytoplasmic and proteinaceous inclusions termed Lewy bodies in the surviving neurons (Davie, ibid and Kumari, ibid). By the time of death, this region will have lost 50-70% of its neurons as compared to an individual without PD.
Lewy bodies are α-synuclein reactive inclusions that are made up of made of several neurofilament proteins combined with proteolytic enzymes. Lewy bodies are found in PD, and a variant of dementia called Dementia with Lewy Bodies, but are not observed in any other neurological diseases.
It appears to have many factors can play a role in disease onset and/or progression of PD. In particular, genes including α-synuclein (PARK1/PARK4, SCNA), parkin (PARK 2), PARK 3, ubiquitin carboxy-terminal hydrolyase L1 (PARK5) etc.) and environmental factors such as exposure to heavy metals and certain pesticides are believed to contribute to PD.
Additionally, genetic mutations in the leucine rich repeat kinase 2 gene (LRRK2, also known as PARK8) has been identified to be involved in both familial and sporatic forms of PD. In fact, studies suggest that LRRK2 mutations may be responsible for between 5 and 13% of familial PD, and from 1 to 5% of sporadic PD. The protein itself is a large (>280 kD) multidomain protein containing the following known domains: armadillo (ARM), ankryn (ANK), LRR, Ras of complex proteins (ROC), C-terminal of ROC (COR), mitogen-activated protein kinase and WD40. Thus, LRRK2 contains several protein-protein interactive domains (ARM/ANK, LRR and WD40) suggesting that LRRK2 plays a role in protein complex formation (Kumari, ibid). Several clusters of mutations have been identified which fall across its length of the gene, with the majority of pathological mutations clustering in the enzymatic domains of the protein.
Specifically, the LRRK2 mutation G2019S has been suggested to play an important role in PD in some ethnicities. Although prevalence among Asians, South Africans and some Europeans (of Polish, Greek and German descent) is quite low, among Ashkenazi Jews and North African Arabs, the prevalence is from 37-40%. In the US and the rest of Europe, G2019S accounts for approximately 1-7% of familial PD and 1-3% of sporadic PD in Caucasians (Kumari, ibid). The mutation is autosomal dominant and the lifetime penetrance for the mutation has been estimated at 31.8%. The SNP responsible for this missense mutation in patients is annotated as rs34637584 in the human genome, and is a G to A substitution at the genomic level (6055G>A). The G2019S mutation has been shown to increase LRRK2 kinase activity, and is found in the within the activation domain of the protein (Luzon-Toro, (2007) Hum Mol Genet 16(17) p. 2031).
The α-synuclein protein is an 140 amino acid protein comprising three domains: an N-terminal amphipathic domain comprising repeats of KTKEGV, a central hydrophobic, non-amyloid domain, and an acidic C-terminal domain. Increased gene dosage of α-synuclein has been shown to be in and of itself, a toxic event that leads to PD. Gene duplications of α-synuclein, which lead to increased gene expression, causes rare cases of autosomal dominant PD. The function of the α-synuclein gene (SNCA) in a wild type setting is still unclear, but it appears that it plays a role in the regulation of autophagy (Winslow and Rubensztein (2010, online publication) Autophagy 7:4, p 1-3). It appears that overexpression of the protein inhibits the secretory pathway by a loss of function of the Rab1a protein which is involved in autophagasome formation at a very early stage of the autophagy process. This in turn may lead to the cellular pathologies observed in PD: abnormal protein aggregation, mitochondrial abnormalities, increased levels of reactive oxygen species and increased sensitivity to cell death (Winslow and Rubensztein ibid).
In addition to increased gene dosage of the wild type SCNA gene, three mutations have been found which are also associated with PD. The three mutations, A53T, A30P, and E46K are all localized in the N-terminal domain of the protein, and appear to exacerbate toxic fibril formation (Perkevi et al (2009) The Anatomical Record 292 (12): 1893). However, cellular and transgenic animal models expressing such mutants only partially recapitulate PD pathology. See, Dawson et al. (2010) Neuron 66(5):646-61. Individuals with PD caused by α-synuclein mutation have similar clinical and pathological features of their PD as patients with idiopathic PD, however the onset of symptoms occurs significantly than typically seen with other PD patients (Pankratz and Foroud (2004) Am Soc Exp Neu Ther 1:235-242).
Thus, there remains a need for the development of novel anti-PD strategies to model and treat PD based on investigation of LRRK2 and SCNA mutations.